Nickel-catalyzed switchable arylative/endo-cyclization of 1,6-enynes

Carbo- and heterocycles are frequently used as crucial scaffolds in natural products, fine chemicals, and biologically and pharmaceutically active compounds. Transition-metal-catalyzed cyclization of 1,6-enynes has emerged as a powerful strategy for constructing functionalized carbo- and heterocycles. Despite significant progress, the regioselectivity of alkyne functionalization is entirely substrate-dependent. And only exo-cyclization/cross-coupling products can be obtained, while endo-selective cyclization/cross-coupling remains elusive and still poses a formidable challenge. In this study, we disclose a nickel-catalyzed switchable arylation/cyclization of 1,6-enynes in which the nature of the ligand dictates the regioselectivity of alkyne arylation, while the electrophilic trapping reagents determine the selectivity of the cyclization mode. Specifically, using a commercially available 1,10-phenanthroline as a ligand facilitates trans-arylation/cyclization to obtain seven-membered ring products, while a 2-naphthyl-substituted bisbox ligand promotes cis-arylation/cyclization to access six-membered ring products. Diastereoselective cyclizations have also been developed for the synthesis of enantioenriched piperidines and azepanes, which are core structural elements of pharmaceuticals and natural products possessing important biological activities. Furthermore, experimental and density functional theory studies reveal that the regioselectivity of the alkyne arylation process is entirely controlled by the steric hindrance of the ligand; the reaction mechanism involves exo-cyclization followed by Dowd-Beckwith-type ring expansion to form endo-cyclization products.

Nickel-catalyzed reductive cross-coupling has been emerged as a powerful and straightforward method for constructing carboncarbon bonds [49][50][51][52][53][54] .Furthermore, due to its unique properties, nickel has been used in a range of ligand-controlled divergent transformations [55][56][57] .To address the major remaining challenges of 1,6-enyne cyclization, we were curious whether changing the structure and/or electronegativity of the ligands in nickel catalysts would enable regioselective and switchable arylation of alkynes.Here, we demonstrate that judicious choice of ligands enables the switchable arylation/ cyclization of 1,6-enynes, in which the nature of the ligand dictates the regioselectivity of alkyne arylation, while the electrophilic trapping reagents determine the selectivity of the cyclization mode.Specifically, in the presence of electron-deficient alkenes, using a commercially available 1,10-phenanthroline as a ligand facilitates trans-arylation/endo-cyclization to obtain sevenmembered ring products, while a 2-naphthyl-substituted Bisbox ligand promotes cis-arylation/endo-cyclization to access sixmembered ring products (Fig. 1b).Diastereoselective cyclizations have also been developed for the synthesis of enantioenriched piperidines and azepanes, which are core structural elements of pharmaceuticals and natural products possessing important biological activities.This transformation is modular, with the ligand rather than the substrate precisely determining the regioselectivity of alkyne arylation process, and the electrophilic trapping reagents determining the regioselectivity of cyclization.Such ligand-directed divergent synthesis (LDS) remains hitherto elusive despite persistent interest.

Reaction development
To test our hypothesis, we started our investigation by evaluating the nickel-catalyzed three-component cascade cyclization of 1,6enyne (1) with PhBr (2) and trifluoromethyl alkene (3) (Table 1).After a series of experiments, a combination of NiBr 2 (DME), 1,10-phenanthroline L4, Mn, CsF, and DMA at 60 °C afforded gem-difluoroallylated seven-membered ring product 4 in 63% isolated yield with exquisite regioselectivity (4/5 = 20/1) (entry 1).Inferior results were observed when either TBAI or NaI was used instead of CsF (entries 2 and 3).Lowering the reaction temperature to 40 °C resulted in no reaction, while increasing the reaction temperature to 80 °C resulted in lower yield (entries 4 and 5).Traces, if any, of 4 were observed when Zn was used instead of Mn as the terminal reducing agent (entry 6).Notably, the direct reductive coupling of aryl bromides and trifluoromethyl alkenes in this catalytic system is well suppressed.
We evaluated a range of different ligands with the goal of identifying the conditions for switchable access to the sevenmembered ring product 4 and the six-membered ring product 5. 2,2′-Bipyridine (L1-L3) and 1,10-phenanthroline (L4) favored the formation of 4, especially the latter providing 4 in higher yield and excellent regioselectivity (entries 7-10).Strikingly, under the same reaction conditions as shown in entry 10, the use of relatively electron-rich Pyrox L5 or Bisbox L6 as ligands resulted in a regioselective switch en route to 5, albeit in lower yields (entries 11 and 12).We further synthesized a series of Bisbox ligands with different substituents on the oxazoline ring and examined their performances.The phenyl-substituted ligand L7 showed slightly higher regioselectivity (4/5 = 1/8, entry 13).The benzyl-substituted ligand L8 provided 5 in 58% yield and improved the regioselectivity to 1:15 (entry 14).Using a 2-naphthyl-substituted Bisbox ligand L9, 5 was obtained in 71% isolated yield and excellent regioselectivity (4/5 = 1:28) (entry 15).These results clearly demonstrate that the backbone of the ligand determines the regioselectivity pattern.
Having identified optimal reaction conditions for the ligandcontrolled divergent synthesis of seven-and six-membered ring Endo-cyclization products are rarely obtained.
Limitations:  products, we turned our attention to investigating the scope and limitations of those two protocols.We first explored the trans-arylative/endo cyclization protocol for the selective synthesis of sevenmembered ring products using ligand L4 (Fig. 2).In terms of 1,6enynes, the carbon-tethered and nitrogen-tethered 1,6-enynes were examined, and the corresponding products 6 and 7 were obtained as expected.The molecular structure of 7 was unambiguously confirmed by single-crystal X-ray diffraction analysis.Electron-donating (OMe) or electron-withdrawing groups (CF 3 , CN) on the aromatic ring at the alkyne terminal (R 1 ) were found to be compatible, leading to the corresponding products 8-10 in 49-69% yields.Notably, chlorine substitution on the aromatic ring also proceeded smoothly, affording 11 in 68% yield, providing an opportunity for further derivatization of the obtained product.Complex molecules such as estrone could also be successfully incorporated into product (12).Nonetheless, alkyl-substituted alkynes and terminal alkynes failed to produce the expected products.Introduction of a phenyl group on the alkene moiety did not preclude the transformation (13).
We then evaluated the scope of aryl (pseudo)halides.We were pleased to find that the presence of electron-donating and electronwithdrawing groups at the para or meta position of the aromatic ring did not affect selectivity and efficiency (14-23).Aryl triflate was also tolerated as shown by the efficient formation of product 15.Heteroaryl bromides such as 5-bromo-2-methoxypyridine, 3-bromothiophene, 2bromodibenzofuran, 2-bromodibenzothiophene, 5-bromobenzofuran, 5-bromoindole, and 3-bromocarbazole were all efficiently transformed into the corresponding products (24-30) in satisfactory yields.Yields were determined by 19 F NMR spectroscopy using trifluorotoluene as the internal standard.The values in brackets corresponds to the yields of isolated products after column chromatography on silica gel.
b Ratio determined by 19 F NMR spectroscopy.
The generality of the electron-deficient alkenes was also investigated.Trifluoromethyl alkenes with various useful functional groups, such as cyano, ester, amide, sulfonate, trifluoromethoxy, chloro, and alkoxy on the aromatic ring, could be successfully transferred to the corresponding products (31-40).In addition, quinoline, benzothiophene and carbazole-substituted trifluoromethyl alkenes (41, 42 and 43) were also compatible with the reaction conditions.The seven-membered ring product 44 and 45 were also obtained under the same reaction conditions when electron-deficient alkenes such as acrylate or vinyl sulfone were used respectively.
We next examined the scope of the cis-arylative/endo cyclization protocol for the selective synthesis of six-membered ring products using ligand L9 (Fig. 3).Similar to what we observed with the transarylative/endo cyclization, C-or N-tethered 1,6-enynes had little effect on the reactivity and selectivity, providing the corresponding products (46-47) in 58-63% yields.1,6-Enynes with substituents on the alkene moiety such as phenyl and ester were also compatible (48-49).Both electron-withdrawing (Cl) and electron-donating groups (OMe) on the aromatic ring at the alkyne terminal (R 1 ) were found to be compatible (50-51).
Aryl (pseudo)halides with versatile functional groups were then examined.It is noteworthy to mention that substrates with both electron-donating and withdrawing groups proceed smoothly to afford the corresponding products (52-58) in moderate to good yields.In particular, the p-chlorine substituted product 54 and the 3-bromocarbazole substituted product 59 were both isolated in good yields.
In addition, the compatibility of the transformation with various trifluoromethyl alkenes was evaluated in a robustness screening.A series of valuable functional groups such as cyano, ester, amide, sulfonate, ketone, trifluoromethoxy, chloro, and alkoxy were all welltolerated (60-69).Trifluoromethyl alkenes bearing heterocyclic groups could also be transformed into the desired products 70-73 in moderate yields.In the case of the trifluoromethylalkenes with a strong electron-donating group, the desired defluorinative products 68-72 were isolated in a mixture with the reductive Heck coupling products which retained the trifluoromethyl group.
Enantiomerically pure N-heterocyclic compounds, especially piperidines and azepanes, represent important motifs in pharmaceutically important natural alkaloids 58 .Consequently, it is of great significant to develop reliable synthetic methods for the synthesis of such  heterocycles.We screened a series of chiral ligands in an attempt to render the reaction asymmetric (Supplementary Table 1).Simultaneously controlling the regioselectivity of alkyne migratory insertion and the stereoselectivity of the cyclization process is indeed a very challenging task, and all our attempts resulted in only racemic products.
We turned to developing a solution to obtain enantioenriched piperidines and azepanes by diastereoselective cyclization of substrates with pre-existing stereocenters 59,60 .Enantioenriched 1,6-enyne 74 (e.r.> 99:1) was prepared employing Ellman's auxiliary 61 to test subsequent ligand-controlled arylative cyclization for the divergent synthesis of chiral piperidines and azepanes (Fig. 4a).Excitingly, by a simple ligand switch, enantioenriched piperidines 75-82 and azepanes 83-86 can be obtained, respectively, from the same starting materials in synthetically useful yields and excellent diastereoselectivities (15:1 to > 20:1 d.r.).The absolute configuration of 76 was determined by singlecrystal X-ray diffraction analysis, and that of all other products were assigned accordingly.

Mechanistic investigation
To shed light on the reaction mechanism, we designed a series of experiments as outlined in Fig. 5. First, Ph-Ni(II)Br complex 98 and 99 were synthesized and submitted to the reactions with 1,6-enyne 97 and trifluoromethyl alkene 3 under our standard reaction conditions.The corresponding products 7 and 47 were obtained in 31% and 30% yields, respectively (Fig. 5a).These results clearly demonstrate that active aryl-nickel(II) species are generated during the reaction and that the ligand determines the regioselectivity alkyne arylation.
We further synthesized alkenyl iodide 100 and subjected to the reaction with trifluoromethylalkene 3 under standard conditions.The target product 7 was isolated in 65% yield, evidently confirming the formation of the key alkenyl-nickel intermediate and the involvement of cis/trans isomerization of alkenyl-nickel species during the reaction (Fig. 5b).Deuterium labeling experiments were performed.Reaction of 100 with 5 equivalents of D 2 O afforded the deuterated exo-cyclization product 101-D in 43% yield.Reaction of 100 with trifluoromethylalkene 3 in the presence of 10 equivalents of D 2 O gave product 101-D and 7 in 24% and 49% yield, respectively (Fig. 5c).These deuterated products should result from deuteration of the corresponding organonickel intermediates, suggesting that both 6-exo-cyclization and 7-endocyclization of alkenyl-nickel intermediate appear to be possible.
Three possible reaction pathways are proposed to explain the transformation of six-membered-ring nickel intermediate 103 to seven-membered-ring nickel intermediate 106 in Fig. 5d.Considering that β-carbon elimination from a non-strained metal complex is a high energy process [62][63][64] , a retro 6-exo via β-carbon elimination followed by 7-endo cyclization deemed less probable (Path I, Fig. 5d).
Furthermore, Dowd-Beckwith ring expansion process was also considered (Path III, Fig. 5d) 68,69 , that is, the primary radical intermediate 104 and the tertiary radical intermediate 105 coexist in the reaction system; the type of electrophilic trapping reagents determine the structure of products.When cross-coupling with aryl bromides via an oxidative addition/reductive elimination mechanism, primary radicals 104 are preferred because the process is more sensitive to steric hindrance of ligands.The nucleophilic tertiary radicals 105 are favored when cross-coupling with less hindered electron-deficient alkenes (acrylates or trifluoromethyl alkenes) via Giese addition.
The subsequent pathway for the generated radical INT7B was shown in Fig. 8.The radical induced Dowd-Beckwith-type ring expansion 68,[81][82][83][84][85] through transition TS8B and TS9B, leading to the formation of seven membered ring radical INT9B.After that, INT9B captured by substrate 3 leads to the formation of INT10B with an activation free energy barrier of 7.9 kcal mol −1 .For the enantiomerically pure N-heterocyclic compound 72, the radical addition preferentially occurred at the less steric hindrance to result excellent diastereoselectivities.Owing to the computed high energy barrier  and reductant Mn proceeds to anion INT11B, which is followed by β-F elimination via transition state TS12B with an activation energy of 9.9 kcal mol −1 , yielding the desired product 4.The energy profile for the radical produced by INT5A-exo-L9 is also calculated to obtain product 5 (for the details of the computational data, see Supplementary Fig. 8).The frontier molecular orbital theory is further used to analysis the reactivity of the generated radicals (Fig. 8c).Compared with radical INT7B, the radical INT9B with higher SOMO energy exhibits more nucleophilicity, which should be thermodynamically more favorable to attack electron-deficient alkenes to generate radical INT10B, delivering the desired cyclization products.

Proposed reaction mechanism
Based on the above experimental and DFT studies, a plausible catalytic cycle is outlined in Fig. gives diarylated products.Intermediates C and G undergo Dowd-Beckwith ring expansion to form more stable tertiary radical intermediates D and H, respectively.Finally, radical addition followed by fluorine elimination will furnish the corresponding six-and sevenmembered ring products, respectively.The structure of the final products is related to the nature of the electrophilic trapping reagents.The primary radical G may react preferentially because it is formed first and is more kinetically accessible.The tertiary radicals D and H, although more crowded, are more stable and survive longer in the reaction system.When reacting with ArBr via an oxidative addition/reductive elimination mechanism, primary radicals C and G are preferred because the process is more sensitive to steric hindrance of the ligand.More nucleophilic tertiary radicals D and H are favored when reacting with electron-deficient alkenes such as trifluoromethylalkenes or acrylates via Giese addition.
Then the reaction was stirred at 60 o C until the reaction was complete (monitored by TLC).The resulting mixture was quenched with saturated NH 4 Cl solution (5 mL) and further diluted with water (10 mL).The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under vacuum.The residue was purified by chromatography on silica gel, eluting with PE/EtOAc (50/1 ~5/1) to afford the desired 7-membered ring products.

General procedure for the synthesis of 6-membered ring products
An oven-dried sealed tube equipped with a PTFE-coated stir bar was charged with NiBr 2 (DME) (10 mol%), L9 (20 mol%), trifluoromethyl alkene (0.1 mmol), 1,6-enyne (0.2 mmol), Mn powder (3.0 equiv), aryl bromide (2.0 equiv) and anhydrous DMA (2 mL).The sealed tube was sealed and removed from the glovebox.Then the reaction was stirred at 60 o C until the reaction was complete (monitored by TLC).The resulting mixture was quenched with saturated NH 4 Cl solution (5 mL) and further diluted with water (10 mL).The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under vacuum.The residue was purified by chromatography on silica gel, eluting with PE/EtOAc (50/1 ~5/1) to afford the desired 6-membered ring products.

Data availability
The authors declare that all the data supporting the findings of this work are available within the article and its Supplementary Information files or from the corresponding author upon request.The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers 2220556 (7), 2220555 (46), and 2240774 (74).CIF files and crystal structure data are available in the Supplementary Information and Supplementary Data 1.

Fig. 3 |
Fig. 3 | Scope for cis-arylative cyclization.a Scope of 1,6-enynes; b Scope of aryl halides; c Scope of electron-deficient alkenes.a The ratio of product to reduced Heck product was determined by 19 F NMR spectroscopy.
3 vs 11.3 kcal mol −1 for L4 and 19.4 vs 2.8 kcal mol −1 for L9).Upon adding D 2 O, the generated INT5B-L4-exo can be converted into six-membered skeleton smoothly, consistent with the experimental observation shown in Fig. 6c.Finally, the Ni(II)-alkyl bond of intermediate INT5B-L4-exo and INT5A-L9-exo undergoes homolytic cleavage to generate alkyl radical and Ni(I) species, which was then reduced by the present of Mn to regenerate INT1A, completing nickel catalytic cycle.

9 .Fig. 6 |
Fig. 6 | DFT investigations.a The calculated energy profile of the nickel-catalyzed cycle using ligand L4; b The competitive migratory insertion of aryl-nickel into alkyne with ligand L4 and L9; c The competitive cyclization modes with ligand L4 and L9.

Fig. 8 |Fig. 9 |
Fig. 8 | The computational analysis of the radical INT7B.a The calculated energy profile from radical INT7B to product 3; b The structure of various transition states; c The frontier molecular orbital theory is further used to analysis the reactivity of the generated radicals.